General Information About Childhood Non-Hodgkin Lymphoma (NHL)

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1] For non-Hodgkin lymphoma (NHL), the 5-year survival rate has increased over the same time period from 45% to 87% in children younger than 15 years and from 48% to 82% for adolescents aged 15 to 19 years.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on the Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

On the basis of immunophenotype, molecular biology, and clinical response to treatment, the vast majority of NHL cases occurring in childhood and adolescence fall into three categories:

Incidence

Lymphoma (Hodgkin lymphoma and NHL) is the third most common childhood
malignancy, and NHL accounts for approximately 7% of
cancers in children younger than 20 years in high-income countries.[2,3]

The following factors affect the incidence of NHL in children and adolescents:[2]

Geographic location: In the United States,
about 800 new cases of NHL are diagnosed each year. The incidence is
approximately ten cases per 1 million people per year.

In sub-Saharan Africa, the high incidence of Epstein-Barr virus (EBV)-induced Burkitt lymphoma/leukemia is tenfold to twentyfold higher, resulting in a much higher incidence of NHL.[4]

Age: Although there is no sharp age peak, childhood NHL
occurs most commonly in the second decade of life, and occurs infrequently
in children younger than 3 years.[2] NHL in infants is very rare (1% in Berlin-Frankfurt-Münster [BFM] trials from 1986 to 2002).[5] The incidence of NHL is increasing overall because of a slight increase in the incidence for those aged 15 to 19 years; however, the incidence of NHL in children younger than 15 years has remained constant over the past several decades.[2]

Race: The incidence of NHL is higher in whites than in African Americans, and Burkitt lymphoma/leukemia is more frequent in non-Hispanic whites (3.2 cases/million person-years) than in Hispanic whites (2.0 cases/million person-years).[6]

Sex: Childhood NHL is more common in males than in females, with the exception of primary mediastinal B-cell lymphoma, in which the incidence is almost the same in males and females.[2,7] A review of Surveillance, Epidemiology, and End Results (SEER) data revealed that 2.5 cases per 1 million person-years of Burkitt lymphoma/leukemia were diagnosed in the United States between 1992 and 2008, with more cases in males than in females (3.9:1.1).[2] The incidence of diffuse large B-cell lymphoma increases with age in both males and females. The incidence of lymphoblastic lymphoma remains relatively constant across ages for both males and females.[2]

Histology: The incidence and age distribution of histologic type of NHL according to sex is described in Table 1.

bIn older adolescents, indolent and aggressive histologies (more commonly seen in adult patients) are beginning to be found.

Age (y)

<5

5–9

10–14

15–19

<5

5–9

10–14

15–19

Burkitt

3.2

6

6.1

2.8

0.8

1.1

0.8

1.2

Lymphoblastic

1.6

2.2

2.8

2.2

0.9

1.0

0.7

0.9

DLBCL

0.5

1.2

2.5

6.1

0.6

0.7

1.4

4.9

Other (mostly ALCL)

2.3

3.3

4.3

7.8b

1.5

1.6

2.8

3.4b

Epidemiology

Relatively little data have been published on the epidemiology of childhood NHL. However, known risk factors include the following:

EBV: EBV is associated with most cases of NHL seen in the immunodeficient population.[2] Almost all Burkitt lymphoma/leukemia is associated with EBV in endemic Africa; however, approximately 15% of cases in Europe or the United States will have EBV detectable in the tumor tissue.[8]

Previous neoplasm: NHL presenting as a subsequent neoplasm is rare in pediatrics. A retrospective review of the German Childhood Cancer Registry identified 2,968 children who were newly diagnosed with cancer, 11 of whom (0.3%) were later diagnosed with NHL as a subsequent neoplasm before the age of 19 years.[9] In this small cohort, outcome was similar to patients with de novo NHL when treated with standard therapy.[9]

Anatomy

Unlike adults with NHL who most often present with nodal disease, children typically have extranodal disease involving the mediastinum, abdomen, and/or head and neck, as well as marrow or CNS.[3] For example, in developed countries, Burkitt lymphoma/leukemia occurs in the abdomen (approximately 60% of cases), with 15% to 20% of cases arising in the head and neck.[10,11] This high incidence of extranodal disease substantiates use of the Murphy staging system for pediatric NHL, as opposed to the Ann Arbor staging system.

Diagnostic Evaluation

The following tests and procedures are used to diagnose childhood NHL:

Prognosis and Prognostic Factors for Childhood NHL

In high-income countries and with current treatments, more than 80% of children and adolescents with NHL will survive at least 5
years, although outcome is variable depending on a
number of factors, including clinical stage and histology.[12]

Response to therapy

Response to therapy in pediatric lymphoma is one of the most important prognostic markers. Regardless of histology, pediatric NHL that is refractory to first-line therapy has a very poor prognosis.[13-15]

Burkitt lymphoma/leukemia: One of the most important predictive factors is response to the initial prophase treatment; poor responders (i.e., <20% resolution of disease) had an event-free survival (EFS) of 30%.[16,17] Failure to achieve a complete remission after the initial induction courses has also been shown to adversely affect survival in Burkitt lymphoma/leukemia.[16,17]

Lymphoblastic lymphoma: The presence of a residual mediastinal mass at day 33 or at the end of induction was not found to be associated with a decreased survival in the BFM 90-95 studies, but all patients with less than 70% reduction at end induction had therapy intensified.[18]

International pediatric NHL response criteria have been proposed and require prospective evaluation. However, the clinical utility of these new criteria are under investigation.[19]

As opposed to acute leukemia, the prognostic value of minimal residual disease (MRD) following initiation of the therapy in pediatric NHL remains uncertain and requires further investigation.

Burkitt lymphoma/leukemia: One study suggests inferior outcome for patients with Burkitt lymphoma/leukemia that had detectable MRD after induction chemotherapy,[20] but a positive MRD at end induction was not prognostic in B-cell NHL in 32 MDD-positive patients, possibly because of the low number of relapses.[21]

T-lymphoblastic lymphoma: In a small study, one of ten patients had measurable MRD at end induction and this was the only patient who relapsed.[22]

Anaplastic large cell lymphoma: A retrospective analysis of a collaborative European study showed that after induction, MRD-negative patients had a relapse risk of approximately 20% and an overall survival (OS) rate of approximately 90%. By contrast, MRD-positive patients had a relapse risk of 81% and an OS rate of 65% (P < .001). The presence of MRD is significantly associated with uncommon histologic subtypes containing small cell and/or lymphohistiocytic components.[23][Level of evidence: 2A]

Stage at diagnosis/minimal disseminated disease (MDD)

In general, patients with low-stage disease (i.e., single extra-abdominal/extrathoracic tumor or totally resected intra-abdominal tumor) have an excellent prognosis (a 5-year survival rate of approximately 90%), regardless of histology.[16,18,24-27] Apart from this, the outcome by clinical stage, if the correct therapy is given, does not differ significantly, except for stage IV patients with CNS disease.

A surrogate for tumor burden (i.e., elevated levels of lactate dehydrogenase [LDH]) has been shown to be prognostic in many studies.[16,25,28,29]

MDD is generally defined as submicroscopic bone marrow involvement that is present at diagnosis. MDD is generally detected by sensitive methods such as flow cytometry or reverse transcription–polymerase chain reaction (RT-PCR). Patients with morphologically involved bone marrow with more than 5% lymphoma cells are considered to have stage IV disease.

Burkitt lymphoma/leukemia: The role of MDD remains to be defined. One study suggests MDD to be predictive of outcome,[30] while another study does not.[21]

T-lymphoblastic lymphoma: A Children's Oncology Group (COG) study demonstrated the 2-year EFS for patients who had an MDD level by flow cytometry of less than 1% was 91% compared with 68% if the MDD level was more than 1%, and 52% if the MDD was 5% and greater.[31]

Anaplastic large cell lymphoma: In a retrospective subset analysis of children with anaplastic large cell lymphoma, MDD detected by RT-PCR for the NPM-ALK gene, could be found in 57% of patients at diagnosis and correlated with clinical stage.[32] The presence of MDD was associated with a 46% cumulative incidence of relapse compared with a 15% cumulative incidence of relapse in patients with no marrow involvement.[32] Patients with MDD who achieved MRD negative status before their second course of therapy had an intermediate EFS (69%) compared with MDD-negative patients (82%) and compared with patients with both MDD and positive MRD status (19%).[32]

Sites of disease at diagnosis

In pediatric NHL, some sites of disease appear to have prognostic value, including the following:

Bone marrow and CNS: In general, patients with leukemic involvement (>25% blasts in marrow) or CNS involvement at diagnosis require more intensive therapy.[17,18,33] Although these intensive therapies have improved outcome, patients who present with CNS disease continue to have the worst outcome.[17,18,33,34] Patients with mature B-cell lymphoma/leukemia with CNS disease at presentation have a 3-year EFS of around 70%, while those with marrow involvement alone have a 3-year EFS of 90%.[17,25,29] The combination of CNS involvement and marrow disease appears to impact outcome the most.[17]

Mediastinum: As opposed to adults, mediastinal involvement in children and adolescents with nonlymphoblastic NHL results in an inferior outcome.[12,16,25,29] In children and young adults with primary mediastinal B-cell lymphoma, series have reported a 3-year EFS of 50% to 70%.[25,28,29,35] However, a recent study from the NCI that utilized the dose-adjusted (DA)-EPOCH protocol (etoposide, prednisone, vincristine, and doxorubicin) with rituximab achieved an EFS close to 90%.[36]

Viscera: In anaplastic large cell lymphoma, a retrospective study by the European Intergroup for Childhood NHL (EICNHL) found a high-risk group of patients defined by involvement of mediastinum, skin, or viscera.[37] In a subsequent study analysis from EICNHL utilizing biologic risk factors, the clinical risk features were not found to be significant.[38] In the CCG-5941 (NCT00002590) study for anaplastic large cell lymphoma patients, these clinical risk factors could not be confirmed and only bone marrow involvement predicted inferior progression-free survival (PFS).[39][Level of evidence: 2A]

Bone: Although previously thought to be a poor prognostic site, patients with NHL arising in bone have an excellent prognosis, regardless of histology.[40,41]

Head and Neck: For mature B-cell NHL, OS is comparable to that observed for patients with primary tumors at other sites. Head and neck primary tumors are associated with higher rates of disseminated and CNS disease and lower rates of LDH levels that were more than twofold above the upper limit of normal. Childhood NHL of the head and neck site was not associated with inferior OS.[11]

Skin: The prognostic implication of skin involvement is limited to anaplastic large cell lymphoma and depends on whether the disease is localized to skin. ALK-negative, skin-limited anaplastic large cell lymphoma appears to have an excellent prognosis. However, studies from EICNHL and the COG have demonstrated that skin involvement in systemic anaplastic large cell lymphoma does not appear to have positive prognostic value.[38,39]

Tumor biology

Mature B-cell lymphoma: Compared with treatments for adults, aggressive Burkitt regimens in pediatrics have been used to treat both Burkitt lymphoma/leukemia and large B-cell histologies, resulting in no difference in outcome based on histology.[12,16,25,26,29] The exception is primary mediastinal B-cell lymphoma, which has had an inferior outcome with these regimens.[12,16,25,28,29,35]

For pediatric Burkitt lymphoma/leukemia patients, secondary cytogenetic abnormalities, other than c-myc rearrangement, are associated with an inferior outcome,[43,44] and cytogenetic abnormalities involving gain of 7q or deletion of 13q appeared to have an inferior outcome on the FAB 96 chemotherapy protocol.[44,45] For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcome appears to be worse.[44]

A subset of pediatric diffuse large B-cell lymphoma cases were found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci and has been associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this finding.[46]

T-lymphoblastic lymphoma: For pediatric patients with T-cell lymphoblastic lymphoma, the BFM group reported that loss of heterozygosity at chromosome 6q was observed in 12% of patients (25 of 217) and was associated with unfavorable prognosis (probability of EFS [pEFS], 27% vs. 86%, P <.0001).[47,48] NOTCH1 mutations were seen in 60% of patients (70 of 116) and were associated with favorable prognosis (pEFS, 84% vs. 66%; P = .021). NOTCH1 mutations were rarely seen in patients with loss of heterozygosity in 6q16.[47]

Anaplastic large cell lymphoma: In adults, ALK-negative disease has an inferior outcome; however, in children, the difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated.[49-51] In a series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma, the presence of a small cell or lymphohistiocytic component
was observed in 32% of patients and was significantly associated with a high risk of
failure in the multivariate analysis, controlling for clinical characteristics.[52]

In the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone, the small cell variant of anaplastic large cell lymphoma, as well as other histologic variants, had a significantly increased risk for failure.[51]

Age

NHL in infants is rare (1% in BFM trials from 1986 to 2002).[5] In this retrospective review, the outcome for infants was inferior compared with the outcome for older patients with NHL.[5]

Adolescents have been reported to have inferior outcome compared with younger children.[10,12,53,54] This adverse effect of age appears to be most pronounced for adolescents with diffuse large B-cell lymphoma, and to a lesser degree T-cell lymphoblastic lymphoma, compared with younger children with these diagnoses.[12,54] On the other hand, for patients with Burkitt and Burkitt-like lymphoma/leukemia on the FAB LMB 96 (COG-C5961) clinical trial, adolescent age (≥15 years) was not an independent risk factor for inferior outcome.[29]

Immune response to tumor

An immune response against the ALK protein (i.e., anti-ALK antibody titer) appeared to correlate with lower clinical stage and predicted relapse risk but not OS.[55] A study by the EICNHL, which combined the level of anti-ALK antibody with MDD, demonstrated that newly diagnosed anaplastic large cell lymphoma patients could be reliably stratified into three risk groups (low, intermediate, and all remaining patients), with a PFS of 28%, 68% and 93%, respectively (P < .0001).[38]

Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005. [PUBMED Abstract]

Histopathologic and Molecular Classification of Childhood NHL

In children, non-Hodgkin lymphoma (NHL) is distinct from the more common
forms of lymphoma observed in adults. While lymphomas in adults are more commonly
low or intermediate grade, almost all NHL that occurs in children is high grade.[1-3] The World Health Organization (WHO) classifies NHL according to the following features:[3]

Other types of lymphoma, such as the nonanaplastic large cell peripheral T-cell lymphomas (including T/NK lymphomas), cutaneous lymphomas, and indolent B-cell lymphomas (e.g., follicular lymphoma and marginal zone lymphoma), are more commonly seen in adults and occur rarely in children. The most recent WHO classification has designated pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma as distinct entities from the counterparts observed in adults.[3]

Refer to the following PDQ summaries for more information about the treatment of NHL in adult patients:

Stage Information for Childhood NHL

The Ann Arbor staging system is used for all lymphomas in adults and for Hodgkin lymphoma in pediatrics. However, the Ann Arbor staging system has less prognostic value in pediatric non-Hodgkin lymphoma (NHL), primarily because of the high incidence of extranodal disease. Therefore, the most widely used
staging schema for childhood NHL is that of the St. Jude Children’s Research Hospital (Murphy Staging).[1] A new staging system defines bone marrow and central nervous system (CNS) involvement using modern techniques to document the presence of malignant cells. However, the basic definitions of bone marrow and CNS disease are essentially the same. The clinical utility of this new staging system is under investigation.[2]

Role of Radiographic Imaging in Childhood NHL

Radiographic imaging is essential in the staging of patients with NHL. Ultrasound may be the preferred method for assessment of an abdominal mass, but computed tomography (CT) scan and, more recently, magnetic resonance imaging (MRI) have been used for staging. Radionuclide bone scans may be considered for patients in whom bone involvement is suspected.

The role of functional imaging in pediatric NHL is controversial. Gallium scans have been replaced by fluorine F 18-fludeoxyglucose positron emission tomography (PET) scanning, which is now routinely performed at many centers.[3] A review of the revised International Workshop Criteria comparing CT imaging alone or CT together with PET imaging demonstrated that the combination of CT and PET imaging was more accurate than CT imaging alone.[4,5]

While the International Harmonization Project for PET (now called the International Working Group) response criteria have been attempted in adults, the prognostic value of PET scanning for staging pediatric NHL remains under investigation.[3,6,7] Data support that PET identifies more abnormalities than CT scanning,[8] but it is unclear whether this should be used to upstage pediatric patients and change therapy. The International Working Group has updated their response criteria for malignant lymphoma to include PET, immunohistochemistry, and flow cytometry data.[5,9]

St. Jude Children's Research Hospital (Murphy) Staging

Stage I childhood NHL

In stage I childhood NHL, a single tumor or nodal area is involved, excluding the
abdomen and mediastinum.

Stage II childhood NHL

In stage II childhood NHL, disease extent is limited to a single tumor with
regional node involvement, two or more tumors or nodal areas involved on one side of the
diaphragm, or a primary gastrointestinal tract tumor (completely resected) with or without
regional node involvement.

Stage III childhood NHL

In stage III childhood NHL, tumors or involved lymph node areas occur on both
sides of the diaphragm. Stage III NHL also includes any primary intrathoracic (mediastinal, pleural, or thymic) disease, extensive primary intra-abdominal
disease, or any paraspinal or epidural tumors.

Stage IV childhood NHL

Bone marrow involvement has been defined as 5% malignant cells in an otherwise normal bone marrow, with normal peripheral blood counts and smears. Patients with lymphoblastic lymphoma who have more than 25% malignant cells in the bone marrow are usually considered to have leukemia and may be appropriately treated on leukemia clinical trials.

CNS disease in lymphoblastic lymphoma is defined by criteria similar to that used for acute lymphocytic leukemia (i.e., white blood cell count of at least 5/μL and malignant cells in the cerebrospinal fluid [CSF]). For other types of NHL, the definition of CNS disease is any malignant cell present in the CSF regardless of cell count. The Berlin-Frankfurt-Münster group analyzed the prevalence of CNS involvement in NHL in over 2,500 patients. Overall, CNS involvement was diagnosed in 6% of patients. CNS involvement (percentage of patients) according to NHL subtype was as follows:[10]

Treatment Option Overview for Childhood NHL

Many of the improvements in childhood cancer survival have been made using
combinations of known and/or new agents that have attempted to improve the
best available, accepted therapy. Clinical trials in pediatrics are designed
to compare potentially better therapy with therapy that is currently accepted
as standard. This comparison may be done in a randomized study of two treatment
arms or by evaluating a single new treatment and comparing the results with
those previously obtained with standard therapy.

All children with non-Hodgkin lymphoma (NHL) should be considered for entry
into a clinical trial. Treatment planning by a multidisciplinary team of
cancer specialists with experience treating tumors of childhood is strongly
recommended to determine, coordinate, and implement treatment to achieve
optimal survival. Children with NHL should be referred for treatment by a
multidisciplinary team of pediatric oncologists at an institution with
experience in treating pediatric cancers. Information about ongoing clinical
trials is available from the NCI website.

NHL in children is generally considered to be widely disseminated at diagnosis, even when the tumor is apparently localized; as a result, combination chemotherapy
is recommended for most patients.[1] Exceptions to this treatment strategy include the following:

In contrast to the treatment of adults with NHL, the use of radiation therapy is limited in children with NHL. Study results include the following:

Early studies demonstrated that the routine use of radiation had no benefit for low-stage (I or II) NHL.[2]

It has been demonstrated that prophylactic central nervous system (CNS) radiation can be omitted in pediatric NHL.[3-6]

For patients with anaplastic large cell lymphoma and B-cell NHL who present with CNS disease, radiation can also be eliminated.[5,6]

Radiation therapy may have a role in treating patients who have not had a complete response to chemotherapy. Data to support limiting the use of radiation therapy in pediatric NHL come from the Childhood Cancer Survivor Study.[7] This analysis demonstrated that radiation was a significant risk factor for subsequent neoplasms and death in long-term survivors.

Treatment of NHL in childhood and adolescence has historically been based on histologic subtype of the disease. A study by the Children’s Cancer Group demonstrated that the outcome for lymphoblastic lymphoma was superior with longer acute lymphoblastic leukemia–like therapy, while nonlymphoblastic NHL (Burkitt lymphoma/leukemia) had superior outcome with short, intensive, pulsed therapy, whereas the large cell lymphoma outcome was similar with either approach.[8]

Outcome for recurrent NHL in children and adolescents remains very poor, with the exception of anaplastic large cell lymphoma.[9-13] All patients with primary refractory or relapsed NHL should be
considered for clinical trials.

Mediastinal masses

Patients with large mediastinal masses are at risk for tracheal compression, superior vena caval compression, large pleural and pericardial effusions, and right and left ventricular outflow compression. Thus, cardiac or respiratory arrest is a significant risk, particularly if the patient is placed in a supine position.[14]

Because of the risks of
general anesthesia or heavy sedation, a careful physiologic and radiographic
evaluation of the patient should be completed, and the least invasive
procedure should be used to establish the diagnosis of lymphoma.[15,16] The following procedures may be used:

Bone marrow aspirate and biopsy.

Thoracentesis. If a pleural or pericardial effusion is present, a cytologic diagnosis is
frequently possible using thoracentesis, with confirmation of the diagnosis and cell lineage by flow cytometry.

Lymph node biopsy. In children who present with
peripheral adenopathy, a lymph node biopsy under local anesthesia and in an
upright position may be possible.[17]

In situations when the above
procedures do not yield a diagnosis, use of a computed tomography (CT)-guided core-needle biopsy should be considered. This procedure can frequently be performed using light sedation and local anesthesia before proceeding to more
invasive procedures. Care should be taken to keep patients out of a supine position. Most procedures, including CT scans and echocardiograms, can be done with the patient on his or her side or prone. Mediastinoscopy, anterior mediastinotomy, or thoracoscopy
are the procedures of choice when other diagnostic modalities fail to establish
the diagnosis. A formal thoracotomy is rarely, if ever, indicated for the
diagnosis or treatment of childhood lymphoma.

Occasionally, it will not be
possible to perform a diagnostic operative procedure because of the risk of
general anesthesia or heavy sedation. In these situations, preoperative
treatment with steroids or, less commonly, localized radiation therapy should be considered.
Because preoperative treatment may affect the ability to obtain an accurate
tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risk of
general anesthesia or heavy sedation is reduced.

Tumor lysis syndrome

Tumor lysis syndrome results from rapid breakdown of malignant cells, causing a number of metabolic abnormalities, most notably hyperuricemia,
hyperkalemia, and hyperphosphatemia. Tumor lysis syndrome may present before the start of therapy.

Hyperhydration and allopurinol or
rasburicase (urate oxidase) are essential components of therapy in all patients, except those with the most limited disease.[18-23] In patients with G6PD deficiency, rasburicase may cause hemolysis or methemoglobinuria. An initial prephase consisting of low-dose
cyclophosphamide and vincristine does not obviate the need for
allopurinol or rasburicase and hydration.

Hyperuricemia and tumor lysis syndrome,
particularly when associated with ureteral obstruction, frequently result in
life-threatening complications.

Tumor Surveillance

Although the use of positron emission tomography (PET) to assess rapidity of response to therapy appears to have prognostic value in Hodgkin lymphoma and some types of NHL observed in adult patients, it remains under investigation in pediatric NHL. To date, there are insufficient data in pediatric NHL to support that early response to therapy assessed by PET has prognostic value.

Diagnosing relapsed disease based solely on imaging requires caution because false-positive results are common.[24-26] There are also data demonstrating that PET scanning can produce false-negative results.[27] A study of young adults with primary mediastinal B-cell lymphoma demonstrated that among 12 patients who had residual mediastinal masses at the end of therapy, 9 of the 12 had positive PET scans. Seven of these nine patients had the masses resected, but no viable tumor was found.[28] Before undertaking changes in therapy based on residual masses noted by imaging, a biopsy to prove residual disease is warranted.[29]

Special Considerations for the Treatment of Children With Cancer

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[30] Children and adolescents with
cancer should be referred to medical centers that have a multidisciplinary team
of cancer specialists with experience treating the cancers that occur during
childhood and adolescence. This multidisciplinary team approach incorporates the skills
of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation
that will achieve optimal survival and quality of life:

Guidelines for
pediatric cancer centers and their role in the treatment of children with
cancer have been outlined by the American Academy of Pediatrics.[31] At these
pediatric cancer centers, clinical trials are available for most of the
types of cancer that occur in children and adolescents, and the opportunity to
participate in these trials is offered to most patients/families. Clinical
trials for children and adolescents with cancer are generally designed to
compare therapy that is accepted as the best currently available therapy (standard therapy) with potentially better therapy. Most of the progress made in identifying curative therapies
for childhood cancers has been achieved through clinical trials. Information
about ongoing clinical trials is available from the NCI
website.

Mature B-cell NHL

Burkitt and Burkitt-like Lymphoma/Leukemia

Incidence

Burkitt and Burkitt-like lymphoma/leukemia in the United States accounts for about 40% of childhood non-Hodgkin lymphoma (NHL) and exhibits a consistent, aggressive clinical behavior.[1-3] The overall incidence of Burkitt lymphoma/leukemia in the United States is 2.5 cases per 1 million person-years and is higher among boys than girls (3.9 vs. 1.1).[2,4] (Refer to Table 1 for more information on the incidence of Burkitt lymphoma by age and sex distribution.)

Tumor biology

The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin, most bearing a clonal surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD19, CD20, CD22) are usually present, and most childhood Burkitt and Burkitt-like lymphomas/leukemias express CALLA (CD10).[1]

Burkitt lymphoma/leukemia expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the c-myc oncogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of c-myc, a gene involved in cellular proliferation.[3,5,6] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.[7]

The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma/leukemia consists of uniform, small, noncleaved cells, whereas the diagnosis of Burkitt-like lymphoma/leukemia is highly disputed among pathologists because of features that are consistent with diffuse large B-cell lymphoma.[8]

Cytogenetic evidence of c-myc rearrangement is the gold standard for diagnosis of Burkitt lymphoma/leukemia. For cases in which cytogenetic analysis is not available, the World Health Organization (WHO) has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma/leukemia or with more pleomorphism, large cells, and a proliferation fraction (i.e., MIB-1 or Ki-67 immunostaining) of 99% or greater.[1] BCL2 staining by immunohistochemistry is variable. The absence of a translocation involving the BCL2 gene does not preclude the diagnosis of Burkitt lymphoma/leukemia and has no clinical implications.[9]

Studies have demonstrated that the vast majority of Burkitt-like or atypical Burkitt lymphoma/leukemia has a gene expression signature similar to Burkitt lymphoma/leukemia.[10,11] Additionally, as many as 30% of pediatric diffuse large B-cell lymphoma cases will have a gene signature similar to Burkitt lymphoma/leukemia.[10,12]

Clinical presentation

The most common primary sites of disease are the abdomen and the lymphatic tissue of Waldeyer ring.[3,4] Other sites of involvement include testes, bone, skin, bone marrow, and central nervous system (CNS). While lung involvement does not tend to occur, pleural and peritoneal spread is seen.

The treatment of Burkitt and Burkitt-like lymphoma/leukemia is the same as treatment for diffuse large B-cell lymphoma. The following discussion is pertinent to the treatment of both types of childhood NHL.

Unlike mature B-lineage NHL seen in adults, there is no difference in outcome based on histology (Burkitt or Burkitt-like lymphoma/leukemia or diffuse large B-cell lymphoma). Pediatric Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma are clinically very aggressive and are treated with very intensive regimens.[13-17]

Tumor lysis syndrome is often present at diagnosis or after initiation of treatment. This emergent clinical situation should be anticipated and addressed before treatment is started. (Refer to the Tumor lysis syndrome section in the Treatment Option Overview for Childhood NHL section of this summary for more information.)

Current treatment strategies are based on risk stratification as described in Table 4. Involvement of the bone marrow may lead to confusion as to whether the patient has lymphoma or leukemia. Traditionally, patients with more than 25% marrow blasts are classified as having mature B-cell leukemia, and those with fewer than 25% marrow blasts are classified as having lymphoma. It is not clear whether these arbitrary definitions are biologically distinct, but there is no question that patients with Burkitt leukemia should be treated with protocols designed for Burkitt leukemia.[13,15]

aBased on results of the FAB-96/LMB study, a serum LDH level more than twice the upper limit of normal has been used to define a group B high-risk group in the international B-NHL study ANHL1131 (NCT01595048).[14]

The following studies have contributed to the development of current treatment regimens for pediatric Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma.

Evidence (chemotherapy):

The Berlin-Frankfurt-Münster (BFM) group has treated risk group R1 (completely resected disease) with two cycles of multiagent chemotherapy (GER-GPOH-NHL-BFM-90 and GER-GPOH-NHL-BFM-95).[13,19] For unresected stage I or stage II disease (R2), patients received a cytoreductive phase followed by five cycles of chemotherapy.[13,19]

In the NHL-BFM-90 study, it was shown that reducing the dose of methotrexate did not affect the results for low-stage disease.[19]

In the NHL-BFM-95 study, it was demonstrated that prolonging the duration of methotrexate infusion did not improve outcome for patients with low-stage disease.[13]

Event-free survival (EFS) with best therapy in NHL-BFM-95 was more than 95% for R1 and R2 group patients.[13]

In the NHL-BFM-95 study, reducing the infusion time of methotrexate from 24 hours to 4 hours for R3 and R4 group patients resulted in less mucositis, but inferior outcome.[13]

EFS with best therapy in NHL-BFM-95 was 93% for R3 and R4 group patients.[13]

The French Society of Pediatric Oncology and French-American-British (FAB) studies have treated completely resected stage I and abdominal stage II (group A) patients with two cycles of multiagent chemotherapy, without intrathecal chemotherapy (COG-C5961 [FAB/LMB-96]).[18][Level of evidence: 2A]

For unresected stage I through IV disease (group B), the above-mentioned FAB study demonstrated that reducing the duration of therapy to four cycles of chemotherapy after a cytoreduction phase and reducing the cumulative doses of cyclophosphamide and doxorubicin did not affect outcome.[14]

The 3-year EFS was 90% for stage III and 86% for stage IV (CNS-negative) patients.

Patients with a lactate dehydrogenase (LDH) level more than twice the upper limit of normal had an EFS of 86% compared with 96% in those with lower LDH levels.

In group C patients in the FAB study, reduction in cumulative dose of therapy and number of maintenance cycles resulted in inferior outcome.[15]

Patients with leukemic disease only, and no CNS disease, had a 3-year EFS of 90%, while patients with CNS disease at presentation had a 70% 3-year EFS.

Patients who were CNS-positive but marrow-negative did better, with an EFS of 82%, while those with combined marrow and CNS disease at diagnosis had an EFS of only 61%.

This study identified response to prophase reduction as the most significant prognostic factor, with poor responders (i.e., <20% resolution of disease) having an EFS of 30%.

Both the BFM and FAB/LMB studies demonstrated that omission of craniospinal irradiation, even in patients presenting with CNS disease, does not affect outcome (COG-C5961 [FAB/LMB-96] and NHL-BFM-90 [GER-GPOH-NHL-BFM-90]).[13-15,19]

Rituximab is a mouse/human chimeric monoclonal antibody targeting the CD20 antigen. Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma both express high levels of CD20.[5]

There is no standard treatment option for patients with recurrent or progressive disease. For recurrent or refractory B-lineage NHL, survival is generally 10% to 30%.[15,25-29] A review of patients treated on the LMB-89, LMB-96 (NCT00002757), and LMB-2001 trials identified 67 of 1,322 patients who relapsed. A multivariate analysis demonstrated that the following factors were associated with better survival:[29]

One site of disease at relapse.

Diffuse large B-cell lymphoma histology.

Initial good-risk disease (i.e., group A or group B with normal LDH).

Duration of complete remission of more than 6 months.

Treatment options for recurrent Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma include the following:

A study from the United Kingdom for children with relapsed or refractory mature B-cell NHL and B-cell acute lymphoblastic leukemia showed the most favorable outcomes for those who received rituximab and autologous SCT. However, the study could not distinguish whether this relationship reflected that children who survived were those who remained well enough to tolerate chemotherapy and rituximab, achieved a response, and were eligible for transplantation.[35]

The COG conducted a study of 20 patients (14 of whom had Burkitt lymphoma/leukemia) using rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) to treat relapsed/refractory B-cell NHL (Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma).[31][Level of evidence: 3iiA]

Patients not in remission at time of transplant do significantly worse.[32,38] The very poor outcome of patients whose disease is refractory to salvage chemotherapy suggests that a transplant option should not be pursued in these patients.[40]

An analysis of the Center for International
Blood and Marrow Transplant Research data demonstrated the following:[32]

No difference using either autologous or allogeneic donor stem cell sources, with 2-year EFS of 50% for diffuse large B-cell lymphoma and 30% for Burkitt lymphoma/leukemia patients who survived to have a transplant.

Some graft-versus-lymphoma effect has been implied by the lower relapse rate in the allogeneic SCT patients, balanced, however, by the higher treatment-related mortality.

A small, single-center, prospective study used autologous transplantation followed by reduced-intensity allogeneic SCT in relapsed NHL.[33]

Treatment options under clinical evaluation for Burkitt/Burkitt-like leukemia/lymphoma include the following:

APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

Tumor tissue from progression or recurrence must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

General information about clinical trials is also available from the NCI website.

Diffuse Large B-cell Lymphoma

Primary mediastinal B-cell lymphoma, previously considered a subtype of diffuse large B-cell lymphoma, is now a separate entity in the most recent WHO classification. (Refer to the Primary Mediastinal B-cell Lymphoma section of this summary for more information.)

Incidence

Diffuse large B-cell lymphoma is a mature B-cell neoplasm that represents 10% to 20% of pediatric NHL.[2,3,41] Diffuse large B-cell lymphoma occurs more frequently during the second decade of life than during the first decade.[2,42] (Refer to Table 1 for more information on the incidence of diffuse large B-cell lymphoma by age and sex distribution.)

Tumor biology

The World Health Organization (WHO) classification system does not recommend subclassification of diffuse large B-cell lymphoma on the basis of morphologic variants (e.g., immunoblastic, centroblastic).[43]

Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:

The vast majority of pediatric diffuse large B-cell lymphoma cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells, such as the BCL6 gene product and CD10.[7,44,45] The age at which the favorable germinal center subtype changes to the less favorable nongerminal center subtype was shown to be a continuous variable.[46]

Pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene that is seen in adults.[44]

As many as 30% of patients younger than 14 years with diffuse large B-cell lymphoma will have a gene signature similar to Burkitt lymphoma/leukemia.[10,12]

In contrast to adult diffuse large B-cell lymphoma, pediatric cases show a high frequency of abnormalities at the MYC locus (chromosome 8q24), with approximately one-third of pediatric cases showing MYC rearrangement and with approximately one-half of the nonrearranged cases showing MYC gain or amplification.[12,47]

A subset of pediatric diffuse large B-cell lymphoma cases was found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci. Diffuse large B-cell lymphoma cases with an IRF4 translocation were significantly more frequent in children than in adults (15% vs. 2%), were germinal center–derived B-cell lymphomas, and were associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this abnormality.[48]

Clinical presentation

Pediatric diffuse large B-cell lymphoma may present in a manner clinically similar to Burkitt or Burkitt-like lymphoma/leukemia, although it is more often localized and less often involves the bone marrow or CNS.[41,42,49] (Refer to the Clinical presentation section in the Burkitt and Burkitt-like Lymphoma/Leukemia section of this summary for more information.)

Prognostic factors

Treatment options for diffuse large B-cell lymphoma

As in Burkitt and Burkitt-like lymphoma/leukemia, current treatment strategies are based on risk stratification, as described in Table 4. The treatment of diffuse large B-cell lymphoma is the same as the treatment of Burkitt and Burkitt-like lymphoma/leukemia. Refer to the Standard treatment options for Burkitt and Burkitt-like lymphoma/leukemia section of this summary for information on the treatment of diffuse large B-cell lymphoma.

Treatment options under clinical evaluation for diffuse large B-cell lymphoma

Treatment options under clinical evaluation for diffuse large B-cell lymphoma include the following:

APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

Tumor tissue from progression or recurrence must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

General information about clinical trials is also available from the NCI website.

Primary Mediastinal B-cell Lymphoma

Incidence

In the pediatric population, primary mediastinal B-cell lymphoma is predominantly seen in older adolescents, accounting for 1% to 2% of all pediatric NHL cases.[42,50-52]

Tumor biology

Primary mediastinal B-cell lymphoma was previously considered a subtype of diffuse large B-cell lymphoma, but is now a separate entity in the most recent World Health Organization (WHO) classification.[53] These tumors arise in the mediastinum from thymic B-cells and show a diffuse large cell proliferation with sclerosis that compartmentalizes neoplastic cells.

Primary mediastinal B-cell lymphoma can be very difficult to distinguish morphologically from the following types of lymphoma:

Diffuse large B-cell lymphoma: Cell surface markers are similar to the ones seen in diffuse large B-cell lymphoma, such as CD19, CD20, CD22, CD79a, and PAX-5. Primary mediastinal B-cell lymphoma often lacks cell surface immunoglobulin expression but may display cytoplasmic immunoglobulins. CD30 expression is commonly present.[53]

Hodgkin lymphoma: Primary mediastinal B-cell lymphoma may be difficult to clinically and morphologically distinguish from Hodgkin lymphoma, especially with small mediastinal biopsies because of extensive sclerosis and necrosis.

Primary mediastinal B-cell lymphoma is associated with distinctive chromosomal aberrations (gains in chromosomes 9p and 2p in regions that involve JAK2 and c-rel, respectively) [51,52] and commonly shows inactivation of SOCS1 by either mutation or gene deletion.[54,55] Primary mediastinal B-cell lymphoma has a distinctly different gene expression profile from diffuse large B-cell lymphoma, but its gene expression profile has features similar to those seen in Hodgkin lymphoma.[56,57]

Clinical presentation

As the name would suggest, primary mediastinal B-cell lymphoma occurs in the mediastinum. The tumor can be locally invasive (e.g., pericardial and lung extension) and can be associated with the superior vena caval syndrome. The tumor can disseminate outside the thoracic cavity with nodal and extranodal involvement, with predilection to the kidneys; however, CNS and marrow involvement are exceedingly rare.[53]

Treatment options for primary mediastinal B-cell lymphoma

Pediatric and adolescent patients with stage III primary mediastinal large B-cell lymphoma did significantly worse on the FAB/LMB-96 (NCT00002757) study, with a 5-year EFS of 66% compared with 85% for adolescents with nonmediastinal diffuse large B-cell lymphoma.[58][Level of evidence: 2A] Similarly on NHL-BFM-95, patients with primary mediastinal B-cell lymphoma had an EFS of 50% at 3 years.[13] However, a study of young adults treated with DA-EPOCH-R showed excellent disease-free survival.[59]

Evidence (DA-EPOCH-R):

A single-arm study in young adults utilized the DA-EPOCH-R regimen (usually six cycles) with filgrastim and no radiation therapy.[59][Level of evidence: 2A]

The 5-year EFS was 93% and overall survival (OS) was 97%.

At short-term follow-up, there was no evidence of cardiac toxicity, despite a high cumulative dose of doxorubicin for those who went through most of the anthracycline-dose escalations.

An important finding in this study was the prognostic value of end-of-therapy imaging. Among 12 patients who had residual mediastinal masses at the end of therapy, 9 of the 12 had positive positron emission tomography scans. Seven of these nine patients had the masses resected, but no viable tumor was found.

A concern for using this regimen is the significantly higher cumulative doses of alkylating agents and anthracyclines administered than used in previous regimens.

A single-arm modification of DA-EPOCH-R (usually six cycles with filgrastim and no radiation therapy) was completed by the BFM group, in which the cumulative doxorubicin dose was kept at 360 mg/m2 and intrathecal chemotherapy was added.[60]

The study showed a 2-year OS of 92% among the 15 consecutive pediatric patients treated.

Treatment options under clinical evaluation for primary mediastinal B-cell lymphoma include the following:

APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

Tumor tissue from progression or recurrence must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005. [PUBMED Abstract]

Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007. [PUBMED Abstract]

Lymphoblastic Lymphoma

Incidence

Lymphoblastic lymphoma comprises approximately 20% of childhood non-Hodgkin lymphoma (NHL).[1-3] (Refer to Table 1 for more information on the incidence of lymphoblastic lymphoma by age and sex distribution.)

Tumor Biology

Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.[3,4]

As opposed to pediatric acute lymphoblastic leukemia, chromosomal abnormalities and the molecular biology of pediatric lymphoblastic lymphoma are not well characterized. The Berlin-Frankfurt-Münster group reported that loss of heterozygosity at chromosome 6q was observed in 12% of patients and NOTCH1 mutations were seen in 60% of patients, but NOTCH1 mutations are rarely seen in patients with loss of heterozygosity in 6q16.[5,6]

Clinical Presentation

As many as 75% of patients with T-cell lymphoblastic lymphoma will present with an anterior mediastinal mass, which may manifest as dyspnea, wheezing, stridor, dysphagia, or swelling of the head and neck.

Pleural and/or pericardial effusions may be present, and the involvement of lymph nodes, usually above the diaphragm, may be a prominent feature. There may also be involvement of bone, skin, bone marrow, central nervous system (CNS), abdominal organs (but rarely bowel), and occasionally other sites, such as lymphoid tissue of Waldeyer ring, testes, bone, or subcutaneous tissue. Abdominal involvement is less than what is observed in Burkitt lymphoma/leukemia.

Involvement of the bone marrow may lead to confusion as to whether the patient has lymphoma with bone marrow involvement or leukemia with extramedullary disease. Traditionally, patients with more than 25% marrow blasts are considered to have T-cell ALL, and those with fewer than 25% marrow blasts are considered to have stage IV T-cell lymphoblastic lymphoma. The World Health Organization (WHO) classifies lymphoblastic lymphoma as the same disease as ALL.[7] The debate remains as to whether they truly represent the same disease.[8] It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design.

Patients with low-stage (stage I or stage II) lymphoblastic lymphoma have long-term disease-free survival (DFS) rates of about 60% with short, pulsed chemotherapy followed by 6 months of maintenance, with an overall survival (OS) greater than 90%.[13,14] However, with the use of an ALL approach and induction, consolidation, and maintenance therapy for a total of 24 months, DFS rates higher than 90% have been reported for children with low-stage lymphoblastic lymphoma.[10-12]

Patients with high-stage (stage III or stage IV) lymphoblastic lymphoma have long-term survival rates higher than 80%.[9-11] Mediastinal radiation is not necessary for patients with mediastinal masses, except in the emergency treatment of symptomatic superior vena caval obstruction or airway obstruction. In these cases, either corticosteroid therapy or low-dose radiation is usually employed. (Refer to the Mediastinal masses section of the Treatment Option Overview for Childhood NHL section of this summary for more information.)

Evidence (high-stage treatment regimens for lymphoblastic lymphoma):

In the GER-GPOH-NHL-BFM-90 study, the 5-year DFS was 90%, and there was no difference in outcome between stage III and stage IV patients.[10] Precursor B-cell lymphoblastic lymphoma appeared to have similar results using the same therapy.[2]

In the GER-GPOH-NHL-BFM-95 study, the prophylactic cranial radiation was omitted, and the intensity of induction therapy was decreased slightly.[11]

There were no significant increases in CNS relapses, suggesting cranial radiation may be reserved for patients with CNS disease at
diagnosis.

Of interest, the probability of 5-year
event-free survival (EFS) rates was worse in NHL-BFM-95 (82%) than in NHL-BFM-90 (90%). It was proposed that the major difference in EFS between NHL-BFM-90 and NHL-BFM-95 resulted from the increased number of subsequent neoplasms observed in NHL-BFM-95. NHL-BFM-95 also had a reduction of asparaginase and doxorubicin in induction, which may have affected outcome, although this difference was not statistically different.

A trial (A5971 [NCT00004228]) of stage III and stage IV lymphoblastic lymphoma patients evaluated two strategies for CNS prophylaxis, without the use of CNS irradiation. Patients were randomly assigned to high-dose methotrexate in interim maintenance (BFM-95) or intrathecal chemotherapy throughout maintenance (CCG-BFM).[9][Level of evidence: 1iiA]

The overall incidence of CNS relapse was 1.2% and there was no difference between arms for CNS relapse, DFS, or OS.

The benefit of intensifying induction therapy with increased doses of daunomycin and the addition of cyclophosphamide was also studied in a randomized fashion. Intensification of induction did not improve DFS or OS, but increased grade III and grade IV toxicities.

The Pediatric Oncology Group conducted a trial to test the effectiveness of the addition of high-dose methotrexate in T-cell ALL and T-cell lymphoblastic lymphoma. In the lymphoma patients, high-dose methotrexate did not demonstrate benefit. In the small cohort (n = 66) of lymphoma patients who did not receive high-dose methotrexate, the 5-year EFS was 88%.[15][Level of evidence: 1iiA] Of note, all of these patients received prophylactic cranial radiation therapy, which has been demonstrated not to be required in T-cell lymphoblastic lymphoma patients.[9,11] In this study, the benefit of adding the cardioprotectant dexrazoxane was tested in a randomized fashion. The addition of dexrazoxane did not affect the outcome and showed cardioprotective benefit on the basis of echocardiographic and laboratory assessments.[16][Level of evidence: 2A]

In addition to the NHL-BFM-95 trial, a single-center study reported that patients treated for lymphoblastic lymphoma had a higher incidence of subsequent neoplasms than did patients treated for other pediatric NHL.[17] However, studies from the Children's Oncology Group (COG) and the Childhood Cancer Survivor Study Group do not support this finding.[9,18,19]

A COG phase II study of nelarabine (compound 506U78) as a single agent demonstrated a response rate of 40%.[27]

A BFM study showed a 14% OS for patients relapsing after BFM front-line therapy and all patients who survived had undergone an allogeneic SCT.[23]

A Center for International Blood and Marrow Transplant Research analysis demonstrated that EFS was significantly worse using an autologous (4%) versus allogeneic (40%) donor stem cell source, with all failures resulting from progressive disease.[26]

Treatment options under clinical evaluation for lymphoblastic lymphoma include the following:

NCI-2014-00712; AALL1231 (NCT02112916)(Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage II–IV T-Cell Lymphoblastic Lymphoma): This phase III trial is utilizing a modified augmented BFM regimen for patients aged 1 to 30 years with T-cell ALL. Patients are classified into one of three risk groups (standard, intermediate, or very high) based on morphologic response at day 29, minimal residual disease (MRD) status at day 29 and end of consolidation, and CNS status at diagnosis. Age and presenting leukocyte count are not used to stratify patients. The objectives of the trial include the following:

To compare EFS in patients who are randomly assigned to receive or not to receive bortezomib on a modified augmented BFM backbone. For those randomly assigned to receive bortezomib, it is given during the induction phase (four doses) and again during the delayed intensification phase (four doses).

To determine the safety and feasibility of modifying standard COG therapy for T-cell ALL by using dexamethasone instead of prednisone during the induction and maintenance phases and additional doses of PEG-asparaginase during the induction and delayed intensification phases.

To determine whether prophylactic cranial radiation can be omitted in 85% to 90% of T-cell ALL patients (non–very high risk, non-CNS3) without an increase in relapse risk, compared with historic controls.

To determine the proportion of patients with end consolidation MRD >0.1% who become MRD-negative after intensification therapy using three high-risk BFM blocks that include high-dose cytarabine, high-dose methotrexate, ifosfamide, and etoposide.

COG-AALL0932 (Risk-Adapted Chemotherapy in Younger Patients With Newly Diagnosed Standard-Risk ALL or Localized B-lineage Lymphoblastic Lymphoma): This trial subdivides standard-risk patients into two groups: low risk and average risk. Low risk is defined as the presence of all of the following: NCI-standard risk age/white blood cell count, favorable genetics (e.g., double trisomies or ETV6-RUNX1), CNS1 at presentation, and low MRD (<0.01% by flow cytometry) at day 8 (peripheral blood) and day 29 (marrow). Average risk includes other NCI standard-risk patients excluding those with high day 29 MRD morphologic induction failure or other unfavorable presenting features (e.g., CNS3, iAMP21, low hypodiploidy, MLL translocations, and BCR-ABL).

All patients will receive a three-drug induction (dexamethasone, vincristine, and intravenous [IV] PEG-L-asparaginase) with intrathecal chemotherapy. For postinduction therapy, low-risk patients will be randomly assigned to receive one of the following:

A regimen based on POG-9904 (NCT00005585), including six courses of intermediate-dose methotrexate (1 g/m2) but without any alkylating agents or anthracyclines.

A modified BFM backbone including two interim maintenance phases with escalating doses of IV methotrexate (no leucovorin) and one delayed intensification phase.

The objective is not to prove superiority of either regimen, but rather, to determine whether excellent outcomes (at least 95% 5-year DFS) can be achieved.

All average-risk patients will receive a modified BFM backbone as postinduction treatment. For these patients, the study is comparing, in a randomized fashion, two doses of weekly oral methotrexate during the maintenance phase (20 mg/m2 and 40 mg/m2) to determine whether the higher dose favorably impacts DFS. Average-risk patients are also eligible to participate in a randomized comparison of two schedules of vincristine/dexamethasone pulses during maintenance (del ivered every 4 weeks or every 12 weeks). The objective of this randomization is to determine whether vincristine/dexamethasone pulses can be delivered less frequently without adversely impacting outcome.

APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

Tumor tissue from progression or recurrence must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

Information about ongoing clinical trials is available from the NCI website.

Anaplastic Large Cell Lymphoma

Incidence

Anaplastic large cell lymphoma accounts for approximately 10% of childhood non-Hodgkin lymphoma (NHL) cases.[1] (Refer to Table 1 for more information on the incidence of anaplastic large cell lymphoma by age and sex distribution.)

Tumor Biology

While the predominant immunophenotype of anaplastic large cell lymphoma is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or natural killer-cell surface antigen expression) does occur. The World Health Organization (WHO) classifies anaplastic large cell lymphoma as a subtype of peripheral T-cell lymphoma.[2]

All anaplastic large cell lymphoma cases are CD30-positive. More than 90% of pediatric anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the fusion protein NPM-ALK; the other 15% of cases are composed of variant ALK translocations.[3] Anti-ALK immunohistochemical staining pattern is quite specific for the type of ALK translocation. Cytoplasm and nuclear ALK staining is associated with NPM-ALK fusion protein, whereas cytoplasmic staining only of ALK is associated with the variant ALK translocations.[3]

In adults, ALK-positive anaplastic large cell lymphoma is viewed differently from other peripheral T-cell lymphomas because prognosis tends to be superior.[4] Also, adult ALK-negative anaplastic large cell lymphoma patients have an inferior outcome compared with patients who have ALK-positive disease.[5] In children, however, this difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated. In addition, no correlation has been found between outcome and the specific ALK-translocation type.[6-8]

In a European series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics (hazard ratio, 2.0; P = .002).[7] The prognostic implication of the small cell variant of anaplastic large cell lymphoma was also shown in the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone.[8]

Clinical Presentation

Clinically, systemic anaplastic large cell lymphoma has a broad range of presentations. These include involvement of lymph nodes and a variety of extranodal sites, particularly skin and bone and, less often, gastrointestinal tract, lung, pleura, and muscle. Involvement of the central nervous system (CNS) and bone marrow is uncommon.

Anaplastic large cell lymphoma is often associated with systemic symptoms (e.g., fever, weight loss) and a prolonged waxing and waning course, making diagnosis difficult and often delayed. Patients with anaplastic large cell lymphoma may present with signs and symptoms consistent with hemophagocytic lymphohistiocytosis.[9]

There is a subgroup of anaplastic large cell lymphoma with leukemic peripheral blood involvement. These patients usually exhibit significant respiratory distress with diffuse lung infiltrates or pleural effusions and have hepatosplenomegaly.[10,11]

APO: Doxorubicin, prednisone, and vincristine.[14] This regimen can be administered in the outpatient setting. The duration of therapy is 52 weeks and the cumulative dose of doxorubicin in 300 mg/m2. No alkylator therapy is given.

FRE-IGR-ALCL99: Dexamethasone, cyclophosphamide, ifosfamide, etoposide, doxorubicin, intravenous (IV) methotrexate (3 g/m2 arm), cytarabine, prednisolone, and vinblastine.[19] This regimen usually requires hospitalization for administration. The total duration of therapy is 5 months and the cumulative dose of doxorubicin is 150 mg/m2.

Evidence (treatment of anaplastic large cell lymphoma):

The POG-9219 study for low-stage lymphoma used three cycles of doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP).[18]

A 5-year event-free survival (EFS) of 88% for large cell lymphoma (anaplastic large cell lymphoma and diffuse large B-cell lymphoma) patients was reported.

The FRE-IGR-ALCL99 trial used three cycles of chemotherapy after cytoreductive prophase for patients with stage I completely resected disease. The therapy for patients without complete resection was the same as the therapy for patients with disseminated disease.[20][Level of evidence: 2A]

The minority of stage I patients (6 of 36) had complete resections and there were no treatment failures for these 6 patients.

The 3-year EFS (81%) and overall survival (OS) (97%) for patients without complete resection were not statistically different from the outcomes for patients with higher-stage disease.

The German Berlin-Frankfurt-Münster (BFM) group used six cycles of intensive pulsed therapy, similar to their B-cell NHL therapy (GER-GPOH-NHL-BFM-90 [NHL-BFM-90]).[13,21,22]; [19][Level of evidence: 1iiA] Building on these results, the European Intergroup for Childhood NHL group conducted the FRE-IGR-ALCL99 study (based on the GER-GPOH-NHL-BFM-90 regimen).

Secondly, FRE-IGR-ALCL99 randomly assigned patients to limited vinblastine or prolonged (1 year) vinblastine exposure. Patients who received the vinblastine plus chemotherapy regimen had a better EFS in the first year after therapy (91%) than those who did not receive vinblastine (74%); however, after 2 years of follow-up, the EFS was 73% for both groups.[22][Level of evidence: 1iiDi] This suggests that the longer therapy in the vinblastine group delayed, but did not prevent, relapse.

COG-ANHL0131 (NCT00059839) showed that the addition of vinblastine to the doxorubicin, prednisone, and vincristine (APO) regimen increased toxicity, but did not improve the survival.[8]

The earlier Pediatric Oncology Group (POG) trial (POG-9317) demonstrated no benefit of adding methotrexate and high-dose cytarabine to 52 weeks of the APO regimen.[14]

The Italian Association of Pediatric Hematology/Oncology group used a leukemia-like regimen for 24 months in LNH-92, with similar results as other regimens, although the duration of first remission was prolonged by the longer therapy.[15]

The CCG-5941 study tested an approach similar to LNH-92, with more intensive induction and consolidation with maintenance for 1 year total duration of therapy, with similar outcome and similar significant increase in hematologic toxicity.[16][Level of evidence: 2A]

CNS involvement in anaplastic large cell lymphoma is rare at diagnosis. In an international study of systemic childhood anaplastic large cell lymphoma, 12 of 463 patients (2.6%) had CNS involvement, three of whom had isolated CNS disease (primary CNS lymphoma). For the CNS-positive group who received multiagent chemotherapy, including high-dose methotrexate, cytarabine,
and intrathecal treatment, at a median follow-up of 4.1 years, the EFS was 50% (95% confidence interval, 25%–75%) and OS was 74% (45%–91%). The role of cranial radiation therapy has been difficult to assess.[23]

Treatment Options for Recurrent Anaplastic Large Cell Lymphoma

As opposed to mature B-cell or lymphoblastic lymphoma, the prognosis for recurrent or refractory anaplastic large cell lymphoma is 40% to 60%.[24-26]

There is no standard approach for the treatment of recurrent/refractory anaplastic large cell lymphoma.

Treatment options for recurrent anaplastic large cell lymphoma include the following:

Chemotherapy, followed by autologous SCT or allogeneic SCT if remission can be achieved, has been employed in this setting.[25,26,30-32]

Evidence (autologous vs. allogeneic SCT):

A retrospective study of relapsed or refractory anaplastic large cell lymphoma in patients who received BFM-type first-line therapy, reinduction chemotherapy, followed by autologous SCT reported the following:[26][Level of evidence: 2A]

A 5-year EFS rate of 59% and an OS rate of 77%. However, outcome of patients with bone marrow or CNS involvement, relapse during first-line therapy, or CD3-positive anaplastic large cell lymphoma was poor. These patients may benefit from allogeneic transplantation.

Several additional studies suggest that allogeneic SCT may result in better outcome for refractory/relapsed anaplastic large cell lymphoma.[30,32,33]

Vinblastine
is active as a single agent in recurrent/refractory anaplastic large cell lymphoma; it induced complete remission (CR) in 25 of 30 evaluable patients (83%) in one study.[29] Nine of 25 patients treated with vinblastine alone remained in CR, with median follow-up of 7 years since the end of treatment.[29][Level of evidence:
3iiiA]

Crizotinib, a kinase inhibitor that blocks the activity of the NPM-ALK fusion protein, has been evaluated in children and adults with relapsed/refractory anaplastic large cell lymphoma.[34] Seven of nine children with anaplastic large cell lymphoma treated on the pediatric phase I study of crizotinib achieved complete responses.[35] Although complete responses are common, the necessary duration of therapy remains unclear.[36][Level of evidence: 3iiiDiii]

Brentuximab vedotin has been evaluated in adults with anaplastic large cell lymphoma. A phase II study of adults and adolescents with CD30-positive cancers that administered a dose of 1.8 mg/kg of brentuximab vedotin showed CR rates of approximately 55% to 60% and partial remission rates of 29%.[37]

Treatment Options Under Clinical Evaluation for Anaplastic Large Cell Lymphoma

Treatment options under clinical evaluation for anaplastic large cell lymphoma include the following:

COG-ADVL0912 (Crizotinib in Treating Young Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma): The ALK inhibitor, crizotinib, is under phase I evaluation in children. The study has a stratum for children with ALK and anaplastic large cell lymphoma.

COG-ADVL1212 (NCT01606878) (Crizotinib and Combination Chemotherapy in Treating Younger Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma): This phase I study is evaluating adverse events associated with crizotinib and multiagent chemotherapy and the maximum tolerated dose of crizotinib that can be administered.

APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

Tumor tissue from progression or recurrence must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

Information about ongoing clinical trials is available from the NCI website.

Lymphoproliferative Disease Associated With Immunodeficiency in Children

Incidence

The incidence of lymphoproliferative disease or lymphoma is 100-fold higher in immunocompromised children than in the general population. The cause of such immune deficiencies includes the following:

A genetically inherited defect (primary immunodeficiency).

Secondary to human immunodeficiency virus (HIV) infection.

Iatrogenic following transplantation (solid organ transplantation or allogeneic hematopoietic stem cell transplantation [HSCT]). Epstein-Barr virus (EBV) is associated with most of these tumors, but some tumors are not associated with any infectious agent.

Clinical Presentation

Non-Hodgkin lymphoma (NHL) associated with immunodeficiency is usually aggressive, with most cases occurring in extralymphatic sites and a higher incidence of primary central nervous system (CNS) involvement.[1-4]

Lymphoproliferative Disease Associated With Primary Immunodeficiency

Lymphoproliferative disease observed in primary immunodeficiency usually shows a mature B-cell phenotype and large cell histology.[2] Mature T-cell lymphoma and anaplastic large cell lymphoma have been observed.[2] Children with primary immunodeficiency and NHL are more likely to have high-stage disease and present with symptoms related to extranodal disease, particularly the gastrointestinal tract and CNS.[2]

Treatment options for lymphoproliferative disease associated with primary immunodeficiency include the following:

Chemotherapy.

Allogeneic stem cell transplantation (SCT).

Patients with primary immunodeficiency can achieve complete and durable remissions with standard chemotherapy regimens for NHL, although toxicity is increased.[2] Recurrences in these patients are common and may not represent the same clonal disease.[5] Immunologic correction through allogeneic SCT is often required to prevent recurrences.

Patients with DNA repair defects (e.g., ataxia-telangiectasia) are particularly difficult to treat.[6,7] Cytotoxic agents produce much more toxicity and greatly increase the risk of subsequent neoplasms in these patients. A Berlin-Frankfurt-Münster retrospective study showed the 10-year overall survival rate to be 58% in 38 children with ataxia telangiectasia or Nijmegen-breakage syndrome and acute lymphoblastic leukemia (n = 9), NHL (n = 28), and Hodgkin lymphoma (n = 1). Dosage-reduction of chemotherapeutic drugs was effective and reduced toxic side effects, but did not prevent subsequent neoplasms (10-year incidence, 25%).[8]

HIV-associated NHL

NHL in children with HIV often presents with fever, weight loss, and symptoms related to extranodal disease, such as abdominal pain or CNS symptoms.[1] Most childhood HIV-related NHL is of mature B-cell phenotype but with a spectrum, including primary effusion lymphoma, primary CNS lymphoma, mucosa-associated lymphoid tissue (MALT), Burkitt lymphoma/leukemia, and diffuse large B-cell lymphoma.[9,10]

HIV-associated NHL can be broadly grouped into the following three subcategories:

Systemic (nodal and extranodal). Approximately 80% of all NHL in HIV patients is considered to be systemic.[1]

Primary CNS lymphoma.

Body cavity–based lymphoma, also referred to as primary effusion lymphoma. Primary effusion lymphoma, a unique lymphomatous effusion associated with the human herpesvirus-8 (HHV8) gene or Kaposi sarcoma herpesvirus, is primarily observed in adults infected with HIV but has been reported in HIV-infected children.[11]

Treatment options for HIV-associated NHL

Treatment options for HIV-associated NHL include the following:

Chemotherapy.

In the era of highly active antiretroviral therapy, children with HIV and NHL are treated with standard chemotherapy regimens for NHL, but careful attention to prophylaxis against and early detection of infection is warranted.[1,12,13] Treatment of recurrent disease is based on histology using standard approaches.

Posttransplant Lymphoproliferative Disease (PTLD)

Posttransplant lymphoproliferative disease (PTLD) represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Essentially all PTLD after HSCT is associated with EBV, but EBV-negative PTLD can be seen following solid organ transplant.[3] While most posttransplant lymphoproliferative diseases are of B-cell phenotype, approximately 10% are mature (peripheral) T-cell lymphomas.[4] The B-cell stimulation by EBV may result in multiple clones of proliferating B cells, and both polymorphic and monomorphic histologies may be present in a patient, even within the same lesion of PTLD.[14] Thus, histology of a single biopsied site may not be representative of the entire disease process.

The World Health Organization (WHO) has classified PTLD into the following three subtypes:[4]

Early lesion: Early lesions show germinal center expansion, but tissue architecture remains normal.

Monomorphic PTLD: Histologies observed in the monomorphic subtype are similar to those observed in NHL, with diffuse large B-cell lymphoma being the most common histology, followed by Burkitt lymphoma/leukemia, and with myeloma, plasmacytoma, and Hodgkin-like PTLD occurring rarely. T-cell PTLD is seen in about 10% of PTLD and may be EBV-positive or EBV-negative and is usually of the mature T-cell subtype.[4]

EBV lymphoproliferative disease posttransplant may manifest as isolated hepatitis, lymphoid interstitial pneumonitis, meningoencephalitis, or an infectious mononucleosis-like syndrome. The definition of PTLD is frequently limited to lymphomatous lesions (low stage or high stage), which are often extranodal (frequently in the allograft).[3] Although less common, PTLD may present as a rapidly progressive, high-stage disease that clinically resembles septic shock, which has a poor prognosis; however, the use of rituximab and low-dose chemotherapy may improve the outcome.[15,16]

First-line therapy for PTLD is to reduce immunosuppressive therapy as much as possible.[21,22] However, this may not be possible because of the increased risk for organ rejection or graft-versus-host disease (GVHD).

Rituximab, an anti-CD20 antibody, has been used in the posttransplant setting. In a study of 144 children and adults who developed post-HSCT PTLD, it was reported that approximately 70% of patients who received rituximab survived. Survival was associated with reduction of immunosuppression as well, but older age, extranodal disease, and acute graft-versus-host disease were predictors of poor
outcome.[17][Level of evidence: 3iiiA] Rituximab as a single agent to treat PTLD after organ transplant has demonstrated efficacy in adult patients, but data are lacking in pediatric patients. (Refer to the Posttransplantation Lymphoproliferative Disorder (PTLD) section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

Low-intensity chemotherapy has been effective in EBV-positive, CD20-positive B-lineage PTLD.[16] A Children's Oncology Group study using rituximab plus cyclophosphamide and prednisone in children with PTLD after solid organ transplantation in whom immune suppression was reduced demonstrated a 67% event-free survival.[16][Level of evidence: 2A] Other studies suggest that modified conventional lymphoma therapy is effective for PTLD with c-myc translocations and Burkitt histology.[19,20][Level of evidence: 3iiDiii] Patients with T-cell or Hodgkin-like PTLD are usually treated with standard lymphoma-specific chemotherapy regimens.[23-26]

Anti-rejection therapy is usually decreased or discontinued when chemotherapy is given to avoid excessive toxicity. There are no data to guide the re-initiation of immunosuppressive therapy after chemotherapy treatment. There is little evidence of benefit for chemotherapy following SCT.

Treatment options under clinical evaluation for PTLD

Treatment options under clinical evaluation for lymphoproliferative disease associated with PTLD include the following:

Adoptive immunotherapy with either donor lymphocytes or ex vivo–generated EBV-specific cytotoxic T-cells have been effective in treating PTLD after blood or bone marrow transplant.[27,28] Although this approach has been demonstrated to be feasible in patients with PTLD after solid organ transplant, it has not been demonstrated to be as effective or practical.[29]

Information about ongoing clinical trials is available from the NCI website.

In an attempt to learn more about the clinical and pathologic features of these rare types of pediatric non-Hodgkin lymphoma (NHL), the Children's Oncology Group (COG) has opened a registry study (COG-ANHL04B1). This study banks tissue for pathobiology studies and collects limited data on clinical presentation and outcome of therapy.[2]

Pediatric-type Follicular Lymphoma

Pediatric-type follicular lymphoma is a disease that genetically and clinically differs from its adult counterpart and is recognized by the WHO classification as a separate entity from follicular lymphoma observed commonly in adults.[1] The genetic hallmark of follicular lymphoma is t(14;18)(q32;q21) involving BCL2; however, this translocation must be excluded to make the diagnosis of pediatric-type follicular lymphoma.[1,3-5] Pediatric-type follicular lymphoma predominantly occurs in males, is associated with a high proliferation rate, and is more likely to be localized disease.[3,6,7] In pediatric-type follicular lymphoma, a high-grade component (i.e., grade 3 with high proliferative index such as Ki-67 expression of >30%) resembling diffuse large B-cell lymphoma can frequently be detected at initial diagnosis but does not indicate a more aggressive clinical course in children. As opposed to follicular lymphoma in adults, pediatric-type follicular lymphoma does not transform to diffuse large B-cell lymphoma.[1,3,5,7,8] Limited-stage disease is observed with pediatric-type follicular lymphoma, with cervical lymph nodes and tonsils as common sites, but disease has also occurred in extranodal sites such as the testis, kidney, gastrointestinal tract, and parotid gland.[3-5,8-10]

Pediatric-type follicular lymphoma appears to be molecularly distinct from follicular lymphoma that is more commonly observed in adults. The TNFSFR14 mutations are common in pediatric-type follicular lymphoma and they appear to occur in similar frequency in adult follicular lymphoma. However, MAP2K1 mutations, which are uncommon in adults, are observed in as many as 43% of pediatric-type follicular lymphomas. Other genes (e.g., MAPK1 and RRAS) have been found to be mutated in cases without MAP2K1 mutations, suggesting the MAP kinase pathway is important in the pathogenesis of pediatric-type follicular lymphoma.[7,11-14] Translocations of the immunoglobulin locus and IRF4 and abnormalities in chromosome 1p have also been observed in pediatric-type follicular lymphoma.[11,12]

Treatment options for pediatric-type follicular lymphoma

Pediatric-type follicular lymphoma is rare in children, with only case reports and small case series to guide therapy. The outcome of pediatric-type follicular lymphoma is excellent, with an event-free survival (EFS) of about 95%.[3,5-8,10] In contrast to adult follicular lymphoma, the clinical course is not dominated by relapses.[3,5,8,9]

Treatment options for pediatric-type follicular lymphoma include the following:

Surgery only.

Multiagent chemotherapy.

Studies suggest that for children with stage I disease who had a complete resection, a watch and wait approach without chemotherapy may be indicated. Patients with higher-stage disease also have a favorable outcome with low-intensity and intermediate-intensity chemotherapy, with 94% EFS and 100% overall survival (OS) with a 2-year median follow-up.[2,3,6,7]

Marginal Zone Lymphoma

Marginal zone lymphoma is a type of indolent lymphoma that is rare in pediatric patients. Marginal zone lymphoma can present as nodal or extranodal disease and almost always as low-stage (stage I or stage II) disease. It is unclear whether the marginal zone lymphoma that is observed in pediatric patients is clinicopathologically different from the disease that is observed in adults. Most extranodal marginal zone lymphoma in pediatrics presents as mucosa-associated lymphoid tissue (MALT) lymphoma and may be associated with Helicobacter pylori (gastrointestinal) or Chlamydophila psittaci (conjunctival), previously called Chlamydia psittaci.[15,16]

Treatment options for marginal zone lymphoma

Most pediatric MALT lymphomas require no more than local therapy involving curative surgery and/or radiation therapy.[15,18] Treatment of MALT lymphoma may also include antibiotic therapy which is considered standard treatment in adults. However, the use of antibiotic therapy in children has not been well studied because there are so few cases.

Intralesional interferon-alpha for conjunctival MALT lymphoma has been described.[19]

Primary Central Nervous System (CNS) Lymphoma

Other types of NHL that may be rare in adults and are exceedingly rare in pediatric patients include primary CNS lymphoma. Because of small numbers of patients, it is difficult to ascertain whether the disease observed in children is the same as the disease observed in adults.

Reports suggest that the outcome of pediatric patients with primary CNS lymphoma (OS, 70%–80%) may be superior to that of adults with primary CNS lymphoma.[20-23]

Most children have diffuse large B-cell lymphoma, although other histologies can be observed.

Treatment options for primary CNS lymphoma

Treatment options for primary CNS lymphoma include the following:

Chemotherapy.

Therapy with high-dose intravenous methotrexate and cytosine arabinoside is the most successful, and intrathecal chemotherapy may be needed only when malignant cells are present in the cerebrospinal fluid.[24]

There is a case report of repeated doses of rituximab, both intravenous and intraventricular, being administered to a 14-year-old boy with refractory primary CNS lymphoma, with an excellent
result.[25] This apparently good outcome needs to be confirmed, and similar results have not been observed in adults. It is generally believed that rituximab does not cross the blood-brain barrier.

(Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information on treatment options for nonacquired immunodeficiency syndrome–related primary CNS lymphoma.)

A Japanese study described extranodal NK/T-cell lymphoma, nasal type as the most common peripheral T-cell lymphoma subtype among Japanese children (10 of 21 peripheral T-cell lymphoma cases). In adults, extranodal NK/T-cell lymphoma, nasal type is generally Epstein-Barr virus (EBV)-positive, and 60% of the cases observed in Japanese children were EBV-positive.[31]

Although very rare, gamma-delta hepatosplenic T-cell lymphoma may be seen in children.[29] This tumor has also been associated with children and adolescents who have Crohn disease and have been treated with immunosuppressive therapy; this lymphoma has been fatal in all cases.[32]

Treatment options for peripheral T-cell lymphoma

Optimal therapy for peripheral T-cell lymphoma is unclear for both pediatric and adult patients.

Treatment options for peripheral T-cell lymphoma include the following:

Chemotherapy.

Radiation therapy.

Allogeneic or autologous stem cell transplantation (SCT).

There have been four retrospective analyses of treatment and outcome for pediatric patients with peripheral T-cell lymphoma. The studies have reported the following:

The United Kingdom Children's Cancer Study Group (UKCCSG) reported on 25 children diagnosed over a 20-year period with peripheral T-cell lymphoma, with an approximate 50% 5-year survival rate.[26] The UKCCSG also observed that the use of acute lymphoblastic leukemia–like therapy, instead of NHL therapy, produced a superior outcome.

The COG reported 20 patients older than 8 years treated on Pediatric Oncology Group NHL trials.[27] Eight of ten patients with low-stage disease achieved long-term disease-free survival compared with only four of ten patients with high-stage disease.

The Berlin-Frankfurt-Münster study group reported 38 cases of peripheral T-cell lymphoma acquired over a 26-year period.[29][Level of evidence: 3iiiDiii] Patients with peripheral T-cell lymphoma–not otherwise specified (n = 18), most with advanced disease (stage III [n = 10] and stage IV [n = 5]), were usually treated with anaplastic large cell lymphoma protocols and had a 10-year EFS rate of 61%. Patients with NK/T-cell lymphoma (n = 9) did poorly, with a 10-year EFS rate of 17%. This series also included five patients with hepatosplenic T-cell lymphoma and five patients with subcutaneous panniculitis-like T-cell lymphoma.

Cutaneous T-cell Lymphoma

Primary cutaneous lymphomas are very rare in pediatric patients (1 case per 1 million person-years), but the incidence increases in adolescents and young adults. All histologies of NHL have been observed to involve the skin. Over 80% of cutaneous lymphomas are T-cell or NK-cell phenotype.[33]

In adults, the gamma-delta subtype of subcutaneous panniculitic T-cell lymphoma is associated with a more aggressive course and carries a worse prognosis than does alpha-beta subcutaneous panniculitic T-cell lymphoma.[37] Morbidity and mortality are frequently related to the development of hemophagocytic syndrome, which was reported in one series in adults to occur in 17% of patients with alpha-beta subcutaneous panniculitic T-cell lymphoma and in 45% of patients with gamma-delta subcutaneous panniculitic T-cell lymphoma. The 5-year OS rate is 82% for alpha-beta subcutaneous panniculitic T-cell lymphoma and 11% for gamma-delta subcutaneous panniculitic T-cell lymphoma.[37] Subcutaneous panniculitic T-cell lymphoma is heterogeneous in the pediatric age group and does not necessarily follow the course observed in adults. Management and treatment should be individualized and, in some cases, watchful waiting may be appropriate. Treatment may only be necessary if hemophagocytic syndrome develops.[38] In a series of 11 pediatric patients with subcutaneous panniculitis-like T-cell lymphoma, most presented with multifocal disease (often on the trunk) and systemic symptoms (fever), and there was a frequent association with hemophagocytic syndrome.[39]

The diagnosis of primary cutaneous anaplastic large cell lymphoma can be difficult to distinguish pathologically from more benign diseases such as lymphomatoid papulosis.[40] Primary cutaneous lymphomas are now thought to represent a spectrum of disorders, distinguished by clinical presentation.

Mycosis fungoides is rarely reported in children and adolescents,[41-43] and it accounts for about 2% of all cases. Patients present with low-stage disease, and it appears that the hypopigmented, CD8-positive variant of mycosis fungoides is more common in children than in adults.[44]

Treatment options for cutaneous T-cell lymphoma

Because of the rarity of cutaneous T-cell lymphoma, no standard treatments have been established.

An oral retinoid (bexarotene) has been reported to be active against subcutaneous panniculitis-like T-cell lymphomas in a series of 15 patients from three institutions.[46] In a series of 11 pediatric patients, aggressive polychemotherapy was used in all patients. Nine of 11 patients sustained clinical remission, with a median follow-up of 3.5 years.[39] In general, however, the optimal therapy for non–anaplastic large cell lymphoma cutaneous T-cell lymphoma in childhood is unclear.

Primary cutaneous anaplastic large cell lymphoma usually does not express ALK and may be treated successfully with surgical resection and/or local radiation therapy without systemic chemotherapy.[49] There are reports of surgery alone also being curative for ALK-positive cutaneous anaplastic large cell lymphoma, but extensive staging and vigilant follow-up is required.[50,51]

Mycosis fungoides occurring in pediatric patients may respond to various therapies, including topical steroids, retinoids, radiation therapy, or phototherapy (e.g., narrow-band ultraviolet B treatment), but remission may not be durable.[44,52-54]

Added text about a review of patients treated on the LMB-89, LMB-96, and LMB-2001 trials that identified 67 of 1,322 patients who relapsed and the reported factors that were associated with better survival.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood non-Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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Updated: August
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